CAREER: Chemical Genetic Dissection of Cell Signaling

凭借这一奖项，化学学部生命过程化学项目资助南加州大学张超博士开发一种化学方法来研究细胞中信息转导的机制。为了调整和适应外部环境的行为，细胞依赖于由数千种蛋白质组成的复杂的通信和控制网络。虽然参与这些通讯网络的一些蛋白质在序列和结构上非常相似，但它们经常具有不重叠的功能。序列和结构相似的蛋白质如何在细胞中执行不同的功能，人们知之甚少，部分原因是缺乏能够有效区分这些蛋白质的工具。张博士将研究一种新的方法来解决这个问题。该方法是基于将反应性特征引入感兴趣的蛋白质中，这将使识别该特征的小分子能够选择性地与蛋白质结合。该方法将应用于密切相关蛋白在细胞信号转导中的作用研究。参与该项目的研究生和本科生将接受包括合成化学、生物化学和细胞生物学在内的跨学科培训。该研究项目还将与一项旨在教育高中和大学学生了解艾滋病药物的机制和发展的外展计划有关。本研究的目的是开发一种化学遗传学方法来研究密切相关的细胞信号蛋白的细胞功能。中心前提是，在靶蛋白中引入的活性半胱氨酸残基可以作为亲和力和特异性元件，使鉴定与蛋白质结合的有效和特异性小分子成为可能。基于在南加州大学获得的初步结果，研究人员将测试这一假设。首先，针对BRAF激酶半胱氨酸突变体的特异性亲电抑制剂将首先在体外鉴定，然后在体内研究。同种异构体特异性抑制剂将用于确定两种RAF同种异构体在细胞周期中的作用。该研究有望提供有关细胞基本信号通路的新知识，并揭示重要信号蛋白的新功能。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Chao Zhang from the University of Southern California to develop a chemical approach to investigate the mechanism by which information is transduced in cells. To adjust and adapt their behavior to external environments, cells rely on intricate communication and control networks comprised of thousands of proteins. While some of the proteins which participate in these communication networks are very similar to each other in sequence and structure, they frequently have non-overlapping functions. How proteins similar in sequence and structure carry out distinct functions in the cell is poorly understood, partly due to a lack of tools that can effectively distinguish between these proteins. Dr. Zhang will work on a novel approach to address this problem. The method is based on the introduction of a reactive feature into a protein of interest, which would enable the selective binding to the protein of small molecules that recognize this feature. The new method will be applied in the study of the roles of closely-related proteins in cell signal transduction. The graduate and undergraduate students who will work on this project will receive an interdisciplinary training in diverse fields including synthetic chemistry, biochemistry and cell biology. The research project will also be related to an outreach program aimed at the education of students from high schools and colleges on the mechanism and development of AIDS drugs.The objective of this research is to develop a chemical-genetic approach for the study of the cellular functions of closely-related, cell-signaling proteins. The central premise is that a reactive cysteine residue introduced in the target protein can serve as an affinity- and specificity element, making possible the identification of potent and specific small molecules that bind to the proteins. Building upon preliminary results obtained at the University of Southern California, the researchers will test this premise. First specific electrophilic inhibitors for a cysteine-mutant of BRAF kinase will be identified first in vitro and then studied in vivo. The isoform-specific inhibitors will be used to determine the roles of two RAF isoforms in the cell cycle. The research is expected to provide new knowledge about a fundamental cell-signaling pathway and to reveal novel functions of vital signaling proteins.